Chemo-free treatment of adult patients with Ph-positive acute lymphoblastic leukemia: latest updates from the 2023 ASH annual meeting

The chemo-free concept represents a new direction for managing adult patients with Ph-positive acute lymphoblastic leukemia (Ph + ALL). The tyrosine kinase inhibitors (TKIs), blinatumomab and venetoclax serve as the backbone of chemo-free regimens; several prospective studies involving these drugs have demonstrated high remission rates and promising, albeit short, survival outcomes. This review summarizes the latest updates on chemo-free regimens in the treatment of adult patients with Ph + ALL, presented at the 2023 ASH annual meeting.


Blinatumomab-based treatment
Blinatumomab has gained attention for its effectiveness in clearing measurable residual disease (MRD).However, the optimal timing of its use has yet to be determined.The D-ALBA trial enrolled 63 newly diagnosed adult patients with Ph + ALL who received a combination of steroids and dasatinib for 85 days, followed by 2 to 5 cycles of blinatumomab and dasatinib consolidation and 12 doses of intrathecal (IT) chemotherapy [1].During induction, 15 patients (24%) exhibited an increase in MRD during dasatinib monotherapy, 6 of whom had the T315I mutation and 1 of whom had the E255K mutation.Over a median follow-up of 53 months, nine relapses occurred-4 hematologic, 4 involving the central nervous system (CNS) and 1 nodal.Twenty-four (39%) patients underwent allogeneic stem cell transplantation (allo-SCT) in first complete remission (CR1).The estimated 4-year overall survival (OS) and disease-free survival rates were 80.7% and 75.8%, respectively.To expedite MRD clearance and suppress resistant clones early, the BLIS-SPHALL trial was designed to introduce blinatumomab

To the editor
Tyrosine kinase inhibitors (TKIs) combined with steroids results in high remission rates and minimal toxicity for adult patients with Ph-positive acute lymphoblastic leukemia (Ph + ALL); however, the cure rate remains unsatisfactory.Attempts are being made to design an optimal chemo-free regimen that incorporates new approaches, such as immunotherapy and small-molecule agents.This review summarizes the latest updates on chemo-free treatment regimens from the 2023 ASH annual meeting.Figure 1 displays the protocols of selected studies, and Table 1 lists their outcomes.as early as 6 weeks into the treatment of 17 patients with de novo Ph + ALL [2].No patients showed an increase in MRD during induction.Four patients (24%) underwent allo-SCT in CR1.With a median follow-up of 11.7 months, two patients relapsed-1 with the T315I mutation who experienced extramedullary relapse-and no deaths occurred.
To suppress T315I clones and reduce recurrence in the CNS, several studies involving third-generation TKIs, adding chemotherapy, or increasing the IT chemotherapy dose are being designed.Jordan et al. explored the use of consolidation therapy comprising ponatinib plus blinatumomab (1-2 cycles) and chemotherapy which consisted of 4 cycles of HD-MTX/ID-Ara-C after dasatinib-based induction in 14 patients [3].Three patients (21%) underwent allo-SCT in CR1.With a median follow-up of 15 months, no relapses or deaths occurred.In the experimental group of the GIMEMA ALL2820 trial (n = 58), dasatinib was replaced by ponatinib, which was given for 70 days, followed by ≥ 2 cycles of blinatumomab consolidation and 15 doses of IT chemotherapy [4].The median follow-up was 6.1 months; only one patient, who was CD19 + and had the T315I mutation, relapsed.In the trial conducted by the MDACC Group (n = 62), patients received up to 5 cycles of blinatumomab with ponatinib, followed by 5 years of ponatinib and 12 IT chemotherapy doses.With a median follow-up of 17 months, six patients (10%) relapsed-two with hematological relapse (one with an E225V mutation), one with an extramedullary-only relapse, and three with a CNS-only relapse.Only 1 (3%) patient underwent allo-SCT in CR1, and the estimated 2-year event-free survival (EFS) and OS rates were 77% and 89%, respectively.In a study conducted by Ting Z et al., olverembatinib, a novel third-generation inhibitor, was used in combination with blinatumomab, followed by an additional cycle or allo-SCT (n = 13) [6]; eight (61.5%)patients underwent allo-SCT in CR1.With a median follow-up of 7 months, one patient with E255V relapsed after allo-SCT.The 6-month OS and EFS were 100% and 87.5%, respectively.
It's noteworthy that the proportion of allo-SCT has significantly decreased in studies with ponatinib plus Blinatumomab, yet the survival of Ph + ALL patients remains unaffected or even improved.In the new era, the role allo-SCT as front-line treatment has been challenged, requiring more evidences to drawn definitive conclusion.

Non-blinatumomab-based treatment
An approach currently being investigated by Chinese scholars incorporates venetoclax into a minimal chemobased regimen [7,8].In the study conducted by Gong et al., thirty-one patients have received a combination of venetoclax, olverembatinib, vincristine, and prednisone for 28 days, followed by 2 cycles of venetoclax, olverembatinib and prednisone consolidation [7].With a median follow-up time of 5.8 months, no relapses or deaths have occurred.Xu et al. designed a study based on the combination of olverembatinib, vindesine and prednisone (n = 29), in which patients will receive 3 cycles of this regimen [8].Sixteen (67%) patients underwent allo-SCT in CR1.After a median follow-up of 241 days, one patient died, while all the remaining patients survived without relapse.An alternative novel regimen was the addition of CAR-T cell (CD19 and CD22) therapy to dasatinib/ steroids/vincristine for newly diagnosed Ph + ALL in adults [9].Eighteen patients were enrolled, and the CMR rate increased from 27.8% (5/18) after induction therapy to 72.2% (13/18) after CD19 CAR-T cell therapy, and increased further to 76.9% (10/13) after CD22 CAR-T cell therapy.No patient received allo-SCT.After a median follow-up of 13.5 months, 2 patients experienced relapses, and 14 of the remaining patients were in sustained CMR.The preliminary efficacy results have sparked our imagination in finding a chemo-free approach for Ph + ALL.
In this article, we review the impressive developments in chemo-free treatment strategies in Ph + ALL from ASH 2023.It important to note that the study design of references 3, 7, 8 and 9 involved the use of chemotherapy drugs (e.g., methotrexate and cytarabine consolidation, vincristine/vindesine), which may not entirely align with the chemo-free concept.However, the use of vincristine/ vindesine was only in the first 1-3 courses of treatment, which are close to chemo-free concepts.
In conclusion, the ASH 2023 Annual Meeting demonstrated notable advances in the field of chemo-free therapy in adult patients with Ph + ALL, mainly focusing on the use of new targeted therapies to design an optimal regimen for improving outcomes.

Fig. 1
Fig. 1 Study schema of each trial

Table 1
Chemotherapy-free regimens for adult patients with newly diagnosed Ph + ALL Abbreviations: Pts, Patients; CR, Complete Remission; CRi, Complete remission with incomplete hematologic recovery; m, month; ms, months; CMR, Complete Molecular Remission; DFS; Disease-free Survival; EFS, Event-free Survival; CNS, Central Nervous System; Allo-SCT, allogeneic stem cell transplantation; CR1, First Complete remission; NA, not available.